Randomized Controlled Trial to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension

Liver Cirrhosis Clinical Trial

Official title:

Randomized Trial, Masked, and Placebo Controlled to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01456286
• Other study ID #: TEHYLIC
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: October 17, 2011
• Last updated: October 1, 2013
• Start date: October 2011
• Est. completion date: October 2013

Study information

• Verified date: October 2013
• Source: Fundacion Clinic per a la Recerca Biomédica
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether sapropterin (an oral analogue of tetrahydrobiopterin) could have a role in the treatment of portal hypertension secondary to liver cirrhosis. Sapropterin or placebo will be given for two weeks in patients with liver cirrhosis and clinically significant portal hypertension. Systemic and hepatic hemodynamics studies will be performed at baseline and after the intervention to assess the effect of sapropterin.

Description:

Portal hypertension and its complications (variceal bleeding, encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome) are the main cause of death and liver transplantation in patients with cirrhosis. Diminishing portal hypertension by drugs (beta-blockers) is associated with a protection in the development of complications from portal hypertension. For this reason it is important to investigate and develop drugs that can reduce the portal pressure in liver cirrhosis. Tetrahydrobiopterin has been shown to decrease portal pressure in animal models of cirrhosis by improving intrahepatic resistance and by increasing nitric oxide bioavailability (eNOS co-factor). These effects were not associated to deleterious effects on systemic hemodynamics.

This study aims to test if sapropterin (an oral analogue of tetrahydrobiopterin) can play a role in the management of portal hypertension. For this, patients with liver cirrhosis and clinically significant portal hypertension will be randomized to receive sapropterin or placebo for two weeks. Patients will undergo an hepatic vein catheterization to asses the hepatic venous pressure gradient (HVPG), and those having and HVPG of 10 mmHg or higher will be randomized to receive sapropterin or placebo. Swan-Ganz catheterization, systemic measurements, and hepatic blood flow by indocyanine green method will also be performed. Patients will receive sapropterin or placebo for two weeks at a dosage of 5 mg/kg/d in the first week, increasing to 10 mg/kg/d in the second week if there are no adverse events or intolerance. A second systemic and hepatic hemodynamic study will be performed after 2 weeks of treatment to assess changes.

Changes in laboratory tests, liver function (Child-Pugh and MELD scores), endothelial dysfunction and oxidative stress markers (Von Willebrand Factor, Malondialdehyde) will be monitored during the study. As sapropterin has been never evaluated in cirrhotic patients, tolerance and adverse effects related to the medication will be registered.

The study will be stratified according to previous beta-blocker therapy (receiving or not receiving beta-blockers).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Liver cirrhosis of any etiology diagnosed by biopsy or by clinical-imaging data

• Male or female patients between 18-75 years old in whom hepatic vein catheterization is indicated.

• Clinically significant portal hypertension defined by a HVPG = 10 mmHg.

• Signed informed consent.

Exclusion Criteria:

• End-stage liver failure defined by one of the following: Prothrombin activity < 40% and/or Bilirubin > 5 mg/dl.

• Pregnancy or breastfeeding.

• Concomitant beginning of non-selective beta-blockers (propranolol, nadolol) during the administration of sapropterin. Beta-blockers are not exclusion criteria if they are on stable doses in the previous 6 weeks.

• Treatment with carvedilol or nitrates.

• Previous TIPS or derivative shunt.

• Hepatocellular carcinoma exceeding Milan criteria.

• Spontaneous bacterial peritonitis or any active infection when entering in the study.

• Portal vein thrombosis or cavernomatosis at ultrasound.

• Chronic heart failure, respiratory failure or chronic renal failure (Creatinine >2 mg/dl).

• Previous convulsions or epilepsy.

• Hypersensibility to sapropterin or any of its excipients.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Portal
• Liver Cirrhosis
• Portal Hypertension

Intervention

Drug:
• sapropterin
two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week

Locations

Country	Name	City	State
Spain	Hospital Clínic de Barcelona	Barcelona
Spain	Hospital Ramón y Cajal	Madrid	Madrid Community

Sponsors (1)

Lead Sponsor	Collaborator
Fundacion Clinic per a la Recerca Biomédica

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Hepatic Venous Pressure Gradient	Changes in portal pressure gradient as measured by hepatic vein catheterization, induced by 2 week treatment with sapropterin/placebo	2 weeks	No